Project Summary Insulin-like growth factor 1 (IGF1) plays an important role in breast cancer initiation and progression due to its regulation of cell proliferation, migration, and invasion. These characteristics make the IGF1 receptor (IGF1R) an attractive therapeutic target. Numerous clinical trials have sought to inhibit IGF1R; however, only a subset of patients responded beneficially, due to a lack of biomarkers for positive therapeutic response. To identify biomarkers of response, our lab identified a set of genes regulated by IGF1 (IGF-sig) that showed a correlation between activation of the IGF-sig and poor prognosis in estrogen receptor (ER)-negative breast tumors. To further identify biomarkers of response to IGF1, we performed a proteomic screen in 21 breast cancer cell lines stimulated with IGF1 and recently reported that E-cadherin (CDH1), a major component of the adherens junction (AJ), acts a repressor of IGF1 signaling. In breast cancer, E-cadherin is genetically lost in invasive lobular breast cancer (ILC), a subtype that accounts for ~10-15% of breast cancers. I have demonstrated that siRNA knockdown of E-cadherin enhances the ability of IGF1 to activate the IGF1R and downstream signaling mediators (Akt, ERK). The enhanced signaling also leads to increased cell cycle progression. Additionally, the loss of E-cadherin enhances sensitivity to IGF1R inhibition. Supporting the translational relevance of our observations, we found a correlation between loss of E-cadherin (CDH1) mRNA expression and the activation of the IGF-sig in ILBC tumors. Therefore, I hypothesize that loss of E-cadherin potentiates IGF1R signaling to enhance breast cancer progression and that loss of E-cadherin expression in ILC tumors may highlight a subset of breast tumors susceptible to IGF1R inhibition. I will test this hypothesis with the following two experimental aims: 1. Define the mechanism by which E-cadherin modulates IGF1R signaling. 2. Evaluate the efficacy of IGF1R inhibitor therapy in CDH1-negative cell lines and tumors and determine if the response correlates with activation of IGF1-signature Based on our data, we aim to determine the mechanism behind the signaling interaction between E-cadherin and IGF1R. Preliminary data suggest that this interaction occurs as a result of the formation of the AJ and is dependent on the extracellular domain of E-cadherin. Second, I will evaluate efficacy to IGF1R inhibitors in CDH1-deficient ILC model systems. These studies will characterize how E-cadherin modulates IGF1R signaling with the goal of defining breast tumors that may respond to IGF1R inhibitors.